Pediatric Weight Management

PWM: Adjunct Therapies (2006)

Citation:

Berkowitz RI, Wadden TA, Tershakovec AM, Cronquist JL. Behavior therapy and sibutramine for the treatment of adolescent obesity. JAMA. 2003;289:1805-1812.

PubMed ID: 12684359
 
Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To examine whether increased weight loss in obese adolescents is induced when sibutramine is added to a family-based, behavioral weight control program.
Inclusion Criteria:
  • Boys and postmenarcheal girls aged 13 to 17 years
  • BMI of 32 to 44
Exclusion Criteria:
  • Cardiovascular disease including arrythmias
  • Type 1 or 2 diabetes mellitus
  • Major psychiatric disorders
  • Pregnancy
  • Use of a weight-loss medication or a weight loss of 5 kg or more in the prior 6 months
  • Use of medications promoting weight gain (e.g. oral steriods)
  • Use of medications contraindicated with use of sibutramine
  • Cigarette smoking
Description of Study Protocol:

Recruitment  Strategy not described

Design 

Phase I: 6 month trial with participants randomized to receive sibutramine and behavioral therapy or placebo in addition to behavior therapy

Phase 2: 6 month open label extension trial where all participants received sibutramine in addition to behavior therapy

Blinding used (if applicable)

Participants, parents and all study personnel were blinded to treatment condition during phase one. Only the research pharmacist was aware of group assignment.

Intervention (if applicable)

 Screening process:

  • Adolescent's primary care physician performed a history and physical exam to exclude the noted contraindications.
  • Adolescent, accompanied by a parent or guardian, completed a behavioral assessment conducted by a staff psychologist or psychiatrist.
Phase 1:
  • Behavioral protocol
    • Adolescents in both treatment groups received the same comprehensive family-based behavioral weight-loss program delivered following detailed treatment manuals.
    • Participants attended 13 weekly group sessions followed by 6 biweekly group sessions led by dietitians, psychologists or psychiatrists.
    • Parents met separately in group sessions held on the same schedule as the adolescents' meetings.
  • Nutrition/Physical Activity protocol
    • Adolescents in both treatment groups were instructed to consume a 1200-1500 calorie/day diet of conventional foods, with approximately 30% calories from fat, 15% from protein and the remainder from carbohydrate.
    • Participants were prescribed an eventual goal of walking or engaging in similar aerobic activity for 120 min per week or more.
    • Participants kept daily eating and activity logs that they submitted at each session.
    • Content of the parents' session paralleled that of their children's sessions. Parents praised they adolescents for adhering to the diet and activity program.
  • Medication protocol
    • All participants received placebo (single blind) the first week.
    • At week 2, participants received either placebo or 5 mg/day of sibutramine.
    • At week 3, sibutramine was increased to 10 mg/day.
    • At week 7, sibutramine was increased to 15 mg/day.
Phase 2:
  • Behavioral protocol
    • Group sessions were held biweekly from months 7 to 9 and monthly from months 10 to 12.
    • Parents met separately in group sessions held on the same schedule as the adolescents' meetings.
  • Medication protocol
    • All participants were treated with sibutramine following the same dose titration schedule used in phase 1.

Statistical Analysis

  • Study was powered to detect a 4.0% difference in baseline BMI between the 2 treatment groups. The study was powered using the effect size statistic d (Cohen), defined as the difference between the 2 treatment groups divided by the pooled standard deviation. The pooled standard deviation was estimated to be 5%. Given a 4.0% difference in percentage change in BMI and a standard deviation of 5%, this corresponds to a large effect size (Cohen d = 0.80). Assuming a 2-tail analysis, alpha = 0.05 and a standard deviation of 5%, 93% power was obtained to detect a percentage BMI reduction as small as 4% between the 2 treatment groups.
  • Changes in degree of obesity were evaluated by changes in weight, BMI and BMI z scores as well as by percentage change in initial BMI.
  • Differences between treatment conditions in changes on these measures from baseline to month 6 (phase 1) and from months 7-12 (phase 2) were examined using a 2 x 3 (condition x time) repeated measures analysis of variance.
  • An intention-to-treat analysis was used in which missing data were replaced by the participant's baseline body weight (ie baseline-carried-forward analysis).
  • A completers analysis (with weight data for completers at 6 and 12 months) and a mixed model analysis also were performed.
  • The family-wise error term for each analysis was set at 0.05.
  • P < 0.05 was considered statistically significant.
  • Secondary outcome measures including blood pressure, pulse, and hunger, were analyzed using repeated measures analysis of variance. For each variable, the family-wise error term was set at 0.05. All secondary analyses were conducted using treatment completers. This was done in part to minimize potential masking of changes in blood pressure or pulse that might occur with an intention to treat analysis.
Data Collection Summary:

Timing of Measurements

  Each treatment visit Baseline Month 3 Month 6 Month 9 Month 12
Weight x x x x x x
Height   x x x x x
Hunger evaluation   x x x x x
Lipids, lipoproteins, serum glucose, insulin levels   x x x x x
Electrocardiogram   x x x x x
Systolic, diastolic blood pressure; pulse rate
  x
x
x
x
x
Systolic, diastolic blood pressure; pulse rate: biweekly for the first 8 months, then monthly in addition to the major time points listed above.

Adverse events: assessed and recorded at each medical visit

Dependent Variables

  • Weight
  • BMI
  • BMI Z score
  • Height: measured using standard techniques
  • Waist circumference: measured using standard techniques
  • Lifestyle program adherence: assessed by the number of days food records completed during phase 1
  • Medication adherence: evaluated by pill counts during phase 1
  • Hunger: evaluated with the Eating Inventory
  • Maternal education: assessed using a 6-point scale ranging from some high school to doctoral degree (some high school=1, high school graduate=2, some college=3, college graduate=4, master's degree=5, doctoral degree=6)
  • Lipids, lipoproteins, serum glucose and insulin levels: measured following an overnight fast
  • Electrocardiogram
  • Systolic and diastolic blood pressures, pulse rate: measured with a Dinamap monitor. Assessments were obtained after the adolescent stayed still for at least 5 min. Three readings were taken at 1-min intervals; the second and third measures were averaged.
  • Adverse events: assessed and recorded at each medical visit

Independent Variables

  • Placebo vs sibutramine
  • Behavioral therapy

Control Variables

 maternal BMI or education

Description of Actual Data Sample:

Initial N: 82 randomized (55 girls, 27 boys).

  • 39 randomized to receive behavior therapy and placebo (24 girls, 15 boys)
  • 43 randomized to receive behavior therapy and sibutramine (31 girls, 12 boys)

Attrition (final N): 

Phase 1 Placebo controlled (months 1-6)

  • Of the 39 randomized to behavior therapy and placebo, 34 completed the 6 month assessment
    • 5 withdrew due to:
      • lack of interest and time (3)
      • lack of parental participation (1)
      • adverse effects (medication stopped) (1)
    • 39 included in 6 month primary intention to treat analysis
    • 34 included in 6 month completers analysis
  • Of the 43 randomized to behavior therapy and sibutramine, 40 completed the 6 month assessment
    • 3 withdrew due to lack of interest and time
    • 43 included in 6 month primary intention to treat analysis
    • 40 included in 6 month completers analysis
Phase 2  All participants received sibutramine (months 7-12)
  • Of the 34 completing 6 month assessment (placebo first 6 months), 29 completed 12 month assessment
    • 5 withdrew
      • lost to follow up (1)
      • lack of interest and time (2)
      • lack of parental participation (1)
      • adverse effects (medication stopped) (1)
    • 39 included in primary intention to treat analysis
    • 29 included in 12 month completers analysis
  • Of the 40 completing 6 month assessment (sibutramine first 6 months), 33 completed 12 month assessment
    • 7 withdrew
      • lack of interest and time (2)
      • disappointed with weight loss (2)
      • lack of parental participation (2)
      • unrelated illness (1)
    • 43 included in primary intention to treat analysis
    • 33 included in 12 month completers analysis
Baseline Characteristics: no significant differences between treatment groups on any baseline measures or in attrition from therapy
  Total Sample Behavior Therapy + Placebo Behavior Therapy + Sibutramine
Characteristic N=82 N=39 N=43
Age, mean (SD), yr 14.1 (1.2) 14.1 (1.2) 14.1 (1.3)
Wt, mean (SD), kg 103.6 (15.4) 105.3 (16.2) 102.0(14.7)
Ht, mean (SD), cm 165.4 (8.0) 166.2 (8.4) 164.6 (7.7)
BMI, mean (SD) 37.8 (3.8) 38.0 (3.6) 37.5 (4.0)
BMI z score, mean (SD) 2.4 (0.2) 2.5 (0.2) 2.4 (0.2)
Waist circumference, mean (SD), cm 110.8 (10.0) 111.5 (10.2) 110.3 (9.9)
Female, No. (%) 55 (67.1) 24 (61.5) 31 (72.1)
Male, No. (%) 27 (32.9) 15 (38.5) 12 (27.9)
Race, No. (%)      
White 45 (54.9) 24 (61.5) 21.(48.8)
Black 34 (41.5) 13 (33.3) 21 (48.8)
Other* 3 (3.6) 2 (5.2) 1 (2.3)
Hunger score, mean (SD)** 4.9 (3.3) 5.5 (3.4) 4.5 (3.1)
Maternal BMI, mean (SD) 32.7 (9.6) 34.4 (11.3) 31.2 (7.4)
Maternal level of education, mean (SD) 3.1 (1.1 3.3 (1.2) 2.9 (1.0)
*
Other race included 1 Hispanic and 2 were more than 1 race.
** Hunger scores ranged from 0-14.

Other relevant demographics: Except for the information presented in the baseline characteristics table, nothing else was provided.

Anthropometrics (e.g., were groups same or different on important measures): see baseline characteristics table

Location:

Weight and Eating Disorders Program, University of Pennsylvania School of Medicine, Philadelphia

Summary of Results:

Weight Change and Percentage Reduction in BMI - Phase 1

Changes in degree of obesity at month 6 (intention to treat analysis)

  Median (Range) Change   Mean (SD) Change      
  Behavior Therapy + Placebo Behavior Therapy + Sibutramine Behavior Therapy + Placebo Behavior Therapy + Sibutramine P value* Mean Difference (95% CI)
Variable (n=39) (n=43) (n=39) (n=43)    
Wt, kg  -1.2     (-19.2 to 5.5)
-6.9 (23.8 to 1.2)
 -3.2 (6.1)
-7.8 (6.3)
0.001
4.6 (2.0-7.4)
Change in initial BMI, % -2.8      (-18.7 to 4.7)
-8.0 (-24.4 to 1.1)
-4.0 (5.4)
-8.5 (6.8)
0.001
4.5 (1.8-7.2)
Change in BMI z score -0.1      (-0.6 to 0.1)
-0.2 (-0.9 to 0.0)
-0.1 (0.1)
-0.2 (0.2)
0.003
0.1 (0.04-0.2)
Waist circumference, cm** -2.0      (-19.6 to 8.0)
-6.7 (-25.2 to 1.8)
-2.8 (5.6)
-8.2 (6.9)
<0.001
5.4 (2.5-8.2)
*Between group comparisons
** Behavior therapy + placebo, n=37; Behavior therapy + sibutramine, n=41.

  1.  At month 6 during phase 1 (placebo controlled), participants in the behavior therapy and sibutramine group lost a mean ± SD of 7.8±6.3 kg equal to an 8.5±6.8% reduction in initial BMI. Participants in the behavior therapy and placebo group lost 3.2±6.1 kg equal to a significantly smaller 4.0±5.4% reduction in initial BMI. [Effect size, 0.73; 95% CI (0.28-1.18); P=0.001]
  2. Statistically significant differences between groups were observed in changes in BMI z score and waist circumference.

Number of adolescents achieving at least 5%, 10%, and 15% reductions in initial BMI at month 6 (intention to treat analysis)*

  No. (%)        
  Behavior Therapy + Placebo Behavior Therapy + Sibutramine X2 P value OR (95% CI)
Reduction in Initial BMI, % (n=39) (n=43)      
>5 14 (36) 27 (63) 5.92 0.02 3.0 (1.2-7.4)
>10 6 (15) 17 (40) 5.91 0.02 3.6 (1.2-10.4)
>15 1 (3) 8 (19) 5.39 0.02 8.7 (1.0-73.0)
*Data are cumulative, such that the percentage of participants who lost 5% or more inlcudes those who lost 10% or more and 15% or more.
  1. More than twice as many adolescents in the behavior therapy and sibutramine group reduced their initial BMI by 10% and 15% compared with those treated by behavior therapy and placebo.
Weight Change and Percentage Reduction in BMI - Phase 2 (Months 7-12)
  1. Participants who were originally treated with placebo and were switched to sibutramine lost an additional 1.3±5.4 kg reducing their baseline BMI by an additional 2.4±5.0%.
  2. Participants originally treated with sibutramine who continued medication gained 0.8±10.5 kg equal to a 0.2±5.4% reduction in initial BMI. (BMI decreased despite weight gain because of increases in ht.)
  3. The difference in percentage reduction in BMI between groups approached significance (effect size, -0.22; 95% CI, -0.66 to 0.21; P=0.057.
Total Weight Change and Percentage Reduction in BMI - Months 1-12
  1. Participants treated throughout the study with behavior therapy and sibutramine lost a total of 7.0±9.3 kg equal to an 8.6±9.9% reduction in initial BMI.
  2. Participants in the behavior therapy and placebo group who were switched at month 7 to sibutramine lost a total of 4.5±8.8 kg equal to a 6.4±8.3% reduction in initial BMI.
  3. The difference between groups at month 12 was not significant.
  4. Weight loss was not related at any time to participants' baseline characteristics including maternal BMI or education.
Adherence, Hunger and Weight Loss
  1. Participants in the behavior therapy and sibutramine group monitored their food intake for 58.9±44.9 days (mean+SD) compared with 61.3±38.2 days for those in the behavior therapy and placebo group.
  2. Effects of treatment condition (placebo vs sibutramine) and self-monitoring on percentage reduction in BMI at month 6 were examined using stepwise linear regression. Number of food records completed during this period accounted for 17.7% of the variance (R2=0.177) in the percentage change in BMI. Treatment group accounted for an additional 12.9% (R2=0.129) bringing the total variance explained to 30.6% (R2=0.306, P<0.001).
  3. Participants treated with behavior therapy and sibutramine used 79.1±21.7% of the total pills prescribed during the first 6 months compared with 78.3±15.9% for participants in the behavior therapy and placebo group.
  4. In the behavior therapy and sibutramine group, the total dose of medication taken correlated significantly with percentage reduction in initial BMI at month 6 (r=0.44, P=0.003).
  5. Participants in the behavior therapy and sibutramine group compared with those treated with placebo reported signficantly greater reductions in hunger at month 3 (effect size, 0.39; 95% CI, -0.07 to 0.86; P<0.001) and month 6 (effect size, 0.43; 95% CI, -0.06 to 0.86; P=0.002). Mean±SD changes were -2.1+3.3 vs -0.3+3.2 anad -2.1+3.3 vs -0.71+3.7 at the two periods respectively.
  6. No significant differences in hunger were observed at month 12.

Serum Chemistries

Changes in serum chemistries from baseline values for participants treated with behavior therapy and placebo or sibutramine (completers analysis). Results from the entire cohort were collapsed across conditions because no significant between-group differences were found.

Change from baseline, % (SD).

  Baseline Month 6 P value Month 12 P value
  (n=74) (n=74)*   (n=62)**  
Lipid values, mg/dL          
Triglycerides 101.7 (51.2) -9.3 (36.2) 0.03 -9.0 (36.0) 0.05
Total cholesterol 165.5 (30.0) -3.2 (9.8) 0.01 -2.3 (12.1) 0.14
HDL cholesterol 45.4 (8.9) 2.3 (13.8) 0.16 7.6 (17.7) 0.001
LDL cholesterol 99.8 (26.1) -2.5 (14.9) 0.16 -4.6 (18.3) 0.05
Insulin, microU/ml 27.0 (13.9) -12.8 (44.6) 0.02 -20.2 (42.7) <0.001
Serum glucose, mg/dL 90.3 (8.8) -1.9 (10.8) 0.13 -2.6 (10.5) 0.06
HOMA 6.1 (3.3) -14.8 (47.4) 0.01 -22.8 (43.2) <0.001
Abbreviations: HOMA (homeostasis model assessment of insulin sensitivity) *At baseline and month 6, n=74 except for LDL cholesterol and serum glucose (n=73) and HOMA (n=72).
**At month 12, n=62 except for LDL choleserol (n=61), serum glucose (n=59), HOMA (n=52) and insulin (n=60)
  1. There were no differences between groups during phases 1 or 2 in changes in lipids, triglycerides, serum insulin, serum glucose or homeostasis model of insulin sensitivity (HOMA).
  2. At month 12 there was a significant increase in HDL cholesterol (P=0.001) and significant reductions in serum insulin (P<0.001) and HOMA (P<0.001).
  3. At month 12, there were significant correlations between percentage change in BMI and percentage reduction in total cholesterol (r=0.30, P=0.02), LDL cholesterol (r=0.33, P=0.01), insulin (r=0.30, P=0.02), glucose (r=0.30, P=0.02), triglycerides (r=0.36, P=0.005) and HOMA (r=0.34, P=0.01).
  4. At month 12, percentage reduction in BMI aslos correlated with percentage increase in HDL cholesterol (r=-0.32, P=0.01).

Blood Pressure and Pulse Rate

Completers analysis* Mean (SD)

   Systolic Blood Pressure
 
 
Diastolic Blood Pressure

 
Pulse Rate, Beats/min

 
   Behavior Therapy and Placebo
Behavior Therapy and Sibutramine
P value**
Behavior Therapy and Placebo
Behavior Therapy and Sibutramine
P Value**  Behavior Therapy and Placebo
Behavior Therapy and Sibutramine
P Value**
 Baseline 114.3 (11.3)
113.0 (11.0)
  55.9 (5.8)
56.8 (5.4)
  83.2 (10.1)
79.4 (10.5)
 
 Mo 3
 110.7 (13.4)
114.8 (11.3)
0.02
55.7 (7.1)
58.4 (8.0)
0.23
81.6 (10.3)
85.6 (10.6)
<0.001
 Mo 6
110.3 (10.4)
112.9 (10.9)
0.06
55.3 (6.2)
58.6 (6.7)
0.11
81.2 (11.6)
84.8 (12.5)
0.007
 Mo 12
112.1 (13.8)
110.5 (10.9)
0.23
56.8 (6.2)
58.7 (6.0)
0.33
87.8 (11.3)
82.7 (11.4)
<0.001
*At baseline and month 3, n=36 for behavior therapy and placebo and n=42 for behavior therapy and sibutramine. At months 6 and 12, n=33 and n=27, respectively, for behavior therapy and placebo and n=39 and n=34 for behavior therapy and sibutramine. During months 7-12, behavior therapy and placebo group received sibutramine.
**Represents the difference between treatment conditions between baseline and month 3, baseline and month 6, and months 6-12.
  1. At month 3 in the behavior therapy and placebo group, systolic blood pressure decreased 3.6+8.6 mm Hg compared with a significant increase of 1.8+10.7 mm Hg in the behavior therapy and sibutramine group (effect size, 0.55; 95% CI, 0.10-1.00; P=0.02).
  2. At month 6, values for these 2 groups were -4.0+8.9 mm Hg and 0.4+9.0 mm Hg, respectively. The differences between groups approached significance (effect size, 0.45; 95% CI, -0.02 to 0.92; P=0.06).
  3. There were no other significant differences between groups at any period in changes in systolic or diastolic blood pressure.
  4. Pulse rate increased significantly (5-6/min) at months 3 and 6 in partcipants who received behavior therapy and sibutramine compared with behavior therapy and placeebo. Similarly, during months 7-12, pulse rate increased by 7.6+12.7 per min in partcipaants who were switched from placebo to sibutramine.
  5. During phase I, medication dose was reduced or discontinued in 19 of 43 participants in the behavior therapy and sibutramine group in response to elevations in blood pressure, pulse rate or both.

Adverse Events

   Number (%)
 
   Behavior Therapy and Placebo
Behavior Therapy and Sibutramine
   n=39 n=43
 Adverse Events During Phase 1 (Months 1-6)
   
 Elevated blood pressure and pulse rate
0
3 (7.0)
 
Elevated blood pressure only
0
1 (2.3)
 Elevated pulse rate only
0
1 (2.3)
 Atrial premature beats
1 (2.6)
0
 Tonsillectomy 2 (5.1)
0
 Knee surgery
0
1 (2.3)
 Adverse Events During Phase 2 (Months 7-12)*
   
 Elevated blood pressure and pulse rate
1 (2.6)
0
 Elevated blood pressure only
0
0
 Elevated pulse rate only
1 (2.6)
0
 Ventricular premature beats
1 (2.6)
1 (2.3)
 Cholelithiasis/
cholecystectomy
1 (2.3)
 Ecchymoses 2 (5.1)
0
 Rash, viral
0
1 (2.3)
*Behavior therapy and placebo group received sibutramine during months 7-12.
  1. When adverse events characterized as elevations in blood pressure and pulse rate, blood pressure alone, or pulse rate alone are combined, differences approach signficance (P=0.06).
  2. One participant had ventricular premature complexes (VPCs) after 6 months of treatment with sibutramine. The participant was asymptomatic and had no other significant changes on electrocardiographic exam. The participant continued to have VPCs in the 6 months following discontinuation of sibutramine, following a course similar to that of benign VPCs that may be observed during adolescence. A second participant was observed to have VPCs at month 9, three weeks following discontinuation of medication because of elevations of blood pressure and pulse rate; by month 12, there was no evidence of VPCs.
  3. During the full 12 month study, sibutramine was reduced to 10 mg in 16 participants, to 5 mg in 7 additional participants and discontinued in 10 participants
    • increased blood pressure and/or pulse rate, n=6
    • ecchymoses, n=2
    • ventricular premature complexes, n=1
    • rash of unclear etiology, n=1
Author Conclusion:
  1. The addition of sibutramine with a comprehensive behavioral program induced significantly more weight loss in obese adolescents than traditional behavioral treatment (placebo).
  2. Participants who received both behavior therapy and sibutramine during the first 6 months decreased their initial BMI more than those who received behavior therapy and placebo, and reported significantly greater reductions in hunger.
  3. In the open label phase, BMI decreased an additional 2.4% (during months 7-12) in participants who were switched from placebo to sibutramine, and participants originally treated with sibutramine maintained their weight loss at month 12 with continued use of sibutramine.
  4. Weight loss continued through month 6 in the behavior therapy and sibutramine group then plateaued.
  5. There was a 6.4% decrease in initial BMI at month 12 for participants who started taking placebo and then switched to sibutramine at month 6. This compares with an 8.5% reduction for those participants who started taking sibutramine at month 6 [at beginning of treatment? text is unclear].
  6. Adherence to self-monitoring optimized response to treatment with medication. Participants who adhered closely to the behavioral program and who were treated with sibutramine, achieved the greatest decrease in BMI during the first 6 months.
  7. The addition of sibutramine to a comprehensive behavioral program induced significantly more weight loss than did behavior therapy and placebo.
  8. Until more extensive safety and efficacy data are available, medications for weight loss should be used only on an experimental basis in adolescents and children.
Funding Source:
Reviewer Comments:

Limitations

  • Randomization procedure not described.
  • How often were the adolescents seen for a medical visit? Did the visits correspond with the group sessions? Does treatment visit = medical visit?
  • Dietary and physical activity data not reported. Did the participants meet the prescribed dietary and physical activity goals?
  • Knoll Pharmaceutical Co and Abbott Laboratories manufactured and provided both the placebo and sibutramine for the study.
  • Financial disclosures: Drs Berkowitz and Wadden have served as consultants to Knoll Pharmaceutical and Abbott Laboratories. Dr. Wadden is on the speaker's bureau and has received honoraria from Abbott Laboratories. Drs. Berkowitz, Wadden and Tershakovec have received funding from Knoll Pharmaceutical and Abbott Laboratories.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? No
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) No
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? No
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
9. Are conclusions supported by results with biases and limitations taken into consideration? N/A
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes